Since the discovery by Donne et al. in 1842, blood platelets have been regarded for a long time as a component of blood necessary for hemostasis. Nowadays, it has been revealed that platelets not only simply play the leading role in the hemostatic mechanism but also show clinically noteworthy multifunctional properties such as concern in the realization of arteriosclerosis, circulatory organ diseases including thrombotic diseases, metastasis, inflammation, rejection reaction after transplantation and immune reaction.
In general, therapies for blood reperfusion with pharmaceutical agents or physical methods have been carried out for thrombotic diseases and ischemic diseases. However, a phenomenon in which activation, adhesion and aggregation of platelets are accelerated after carrying out revascularization due to breakdown of vascular tissues including endothelial cells, or collapse of fibrinolysis-coagulation balance or the like caused by the drug itself, has recently been found and causing clinical problems. For example, it has been revealed that after recirculation by a thrombolytic therapy using t-PA or the like, fibrinolysis ability and coagulation ability are activated and systemic coagulation-fibrinolysis balance collapses. Clinically, it results in re-obstruction which has been causing a therapeutically large problem (Non-patent reference 1).
On the other hand, a PTCA therapy or a stent indwelling method has been rapidly popularizing and gaining a certain fruit for the treatment of diseases based on angina pectoris, myocardial infarction and the like coronary artery stricture and aorta stricture. However, since these therapeutic methods damage vascular tissues including endothelial cells, acute coronary obstruction, and further re-stricture which occurs at chronic stage, has been causing problems. Platelets are taking an important role in various thrombolytic ill effects (re-obstruction and the like) after such a revascularization. Thus, effectiveness of an anti-platelet agent is expected, but sufficient effects of the conventional anti-platelet agents have not been confirmed.
As preventive or therapeutic agents for such circulatory organ system diseases, aspirin, cilostazol, prostaglandin I2, prostaglandin E1, ticlopidine, clopidogrel, dipyridamole and the like platelet aggregation inhibitors have been used. Also in recent years, a GPIIb/IIIa antagonist which inhibits the final step of platelet aggregation and has strong platelet aggregation inhibition activity has been developed, but its use is limited to the intravenous drip infusion at thrombosis acute phase (Non-patent reference 2).
In recent years, it has been revealed that, regarding ticlopidine and clopidogrel which are used as anti-platelet agents, these are exerting platelet aggregation inhibitory activity through the inhibition of P2Y12 as an ADP receptor by their active metabolites. Thereafter, a triazolo[4,5-D]pyrimidine derivative (Patent reference 1), piperazine and/or homopiperazine derivatives (Patent Reference 2 and Patent Reference 3), a pyrazolidinedione derivative (Patent Reference 4), an isoquinolinone derivative (Patent Reference 5) and the like have been reported as compounds having P2Y12 inhibitory activity.
On the other hand, Patent References 6 and 7 are known as quinolone derivatives.
In Patent Reference 6, a compound represented by a formula (A) having antimicrobial action is known, but possession of platelet aggregation inhibitory activity by these derivatives is not known. In addition, its structure is different from the compound of the present invention in terms that the moiety which corresponds to R5 of the compound of the present invention is a carboxylic acid, ester or carbamoyl.
(In the formula, R1 represents —OR9, amino group or lower alkylamino group, and R9 hydrogen atom or a carboxy-protecting group. See said official gazette for other symbols.)
In Patent Reference 7, it is reported that a compound represented by a formula (B) has P2Y12 inhibitory activity. However, its structure is different from the compound of the present invention in terms that the moiety which corresponds to R5 of the compound of the present invention is carbamoyl.
(See Said Official Gazette for Symbols in the Formula.)
In Patent Reference 8, it is reported that a compound represented by a formula (C) has P2Y12 inhibitory activity. However, its structure is different from the compound of the present invention in terms that the moiety which corresponds to R5 of the compound of the present invention is carbamoyl.
(See Said Official Gazette for Symbols in the Formula.)    Non-patent reference 1: “Journal of American College of Cardiology”, 1988, vol. 12, p. 616-623    Non-patent reference 2: “Sogo Rinsho (Synthetic Clinic)”, 2003, vol. 52, p. 1516-1521    Patent Reference 1: International Publication WO 00/34283    Patent Reference 2: International Publication WO 02/098856    Patent Reference 3: International Publication WO 03/022214    Patent Reference 4: International Publication WO 05/000281    Patent Reference 5: International Publication WO 05/035520    Patent Reference 6: International Publication WO 98/23592    Patent Reference 7: International Publication WO 05/009971    Patent Reference 8: International Publication WO 06/077851